Diabetes and cardiovascular disease

Patients with type 2 diabetes have a higher risk for heart attack or stroke compared to the general population, so reducing this risk as much as possible should be a central goal of treatment. Cardiovascular disease (CVD) is also the principal cause of death and disability among people with type 2 diabetes globally, with approximately two thirds of deaths in people with diabetes attributable to CVD.¹

Insulin secretion declines with advancing age and this decline may be accelerated by genetic factors. Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors such as dyslipidaemia, hypertension and prothrombotic factors.²

Following the rosiglitazone controversy, the US Food and Drug Administration (FDA) mandated in 2008 that all new anti-diabetic agents must undergo an adequately powered, glycaemic equipoised, cardiovascular outcome trial in high-risk type 2 diabetic patients, during the post-marketing phase to demonstrate its safety by showing non-inferiority against placebo.

This has led to more extensive information being available on the cardiovascular outcomes for new agents available to treat type 2 diabetes.

Why does someone with diabetes have an increased risk of CVD?

The majority of people with type 2 diabetes will eventually succumb to cardiovascular death and it is not down to the established risk factors such as hypertension and hyperlipidaemia. There is something quite fundamental about the type 2 diabetes state that increases the risk of vascular damage. We don’t understand exactly the link, but when treating cardiovascular risk factors in type 2 diabetes patients we tend to have tighter targets and be more aggressive in getting them under control.

We know that people with type 2 diabetes benefit from tight blood pressure, lipid control and also use of antiplatelet agents like aspirin. More recently we are starting to see that different glucose-lowering drugs have a beneficial impact on CVD. This has been controversial over the years as there have also been some studies where tight glucose control tended to make things worse for cardiovascular outcomes rather than better.

What prevalence in the UK is affected?

Type 2 diabetes affects approximately 6–7% of people in the UK amounting to over three million individuals. The diagnosis is predominately made in the middle or later years. Of these, around 15% fit the criteria that have been used in the diabetes cardiovascular outcome trials. It is a huge number of people.

How does the UK fare compared to other countries in terms of diabetes management?

We could be doing more, but there are audits that take place that look at people with type 2 diabetes and their various risk factors. There is evidence of blood pressure recording, year on year, improving gradually. We are probably collecting more data than the majority of European countries and we are probably as good as them.

Is the number of patients with diabetes and CVD likely to increase in the future?

Type 2 diabetes is a disease of ageing and it is driven by increasing weight and obesity. Since obesity is becoming more common and people are living longer then the number of people with diabetes will go up. Although the proportion of people with diabetes and CVD may be coming down, the absolute numbers will increase.

Is this cardiovascular risk lessened if diabetes is controlled by pharmacological agents?

Over the years there has been a lot of controversy about glucose-lowering drugs and CVD. As far back as the 1970s there was evidence that drugs in the sulfonylurea class might actually increase the risk of CVD. There were also queries about insulin and whether that might increase the risk in people in type 2 diabetes. I think the consensus view is that over time if you treat diabetes aggressively from diagnosis it will automatically lead to a reduction in cardiovascular outcomes.

The controversy surrounding rosiglitazone and increased risk of heart attack means that any new agents have to go through cardiovascular outcomes trials to prove their safety in CVD. Over the past couple of years, studies have emerged showing that some glucoselowering agents appear to provide cardiovascular benefits and the survival in patients is actually enhanced by these new drugs.

What agents are most effective in this area?

In the EMPA-REG study, patients with type 2 diabetes at high risk for cardiovascular events who received the sodium glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.³

Another SGLT-2, canagliflozin, was investigated in the CANVAS trial. It found that patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo.⁴

LEADER was another trial that looked into the long-term effects of the glucagon-like peptide-1 (GLP-1) analogue liraglutide in people with type 2 diabetes at high risk of major cardiovascular events. It found that liraglutide statistically significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction or non-fatal stroke by 13% versus placebo, when added to standard of care. The overall risk reduction was derived from a statistically significant 22% reduction in cardiovascular death with liraglutide treatment versus placebo and non-significant reductions in non-fatal myocardial infarction and non-fatal stroke.⁵

The SUSTAIN-6 study investigated the rate of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in patients with type 2 diabetes. The composite primary endpoint was significantly lower among patients receiving the GLP-1 semaglutide than among those receiving placebo, an outcome that confirmed both the noninferiority and superiority of semaglutide.⁶

Since the FDA mandate more than 150,000 patients have been enrolled into cardiovascular outcome studies. They are, with two exceptions, placebo controlled and are a huge amount of work for patients and professionals alike, but we now know more about these new drugs than we ever did about the older ones.

What is the role of diet and exercise in reducing the cardiovascular risks for patients with diabetes?

Ultimately, sedentary lifestyle and obesity are driving the type 2 diabetes epidemic. Having said that the evidence that lifestyle can be effective in type 2 diabetes is quite limited. There is a study called the Look Ahead study⁷ that was published in 2012 where aggressive lifestyle measures such as exercise and diet, over nine years were investigated. The study was halted prematurely as there was no evidence it was going to make any difference. It is probable that people can’t stick to the regime for long enough so the benefits dissipate and disappear. Although we promote lifestyle strong, evidence is not there to support it.

Are there any groups that are at greatest risk in this population?

Studies have focused on people who have either had a cardiovascular event or people who are at higher risk of cardiovascular events. This includes older people, patients with high blood pressure or chronic renal disease. These are the ones that have been included in trials to date. The people at highest risk seem to benefit the most and whether these findings will be extrapolated down to newly diagnosed people remains to be seen. At the moment the way that these new trials have been adopted into clinical practice and guidance changes has been to focus on patients with type 2 diabetes and existing vascular disease. Interestingly, NICE hasn’t made a proclamation on these studies. It was supposed to produce a draft for discussion at the end of August this year and that has been delayed and the subsequent update in December is also delayed. That means that NICE guidance is falling behind other leading Western economies that have produced more up-to-date guidance on the use of newer agents in diabetes management. This could be down to money as the newer drugs are more expensive and this would increase drug expenditure. There will be a massive impact when NICE makes a statement as clinical commissioning groups will need to take this decision on board. Until then the payers have an excuse to ignore modern day drugs.

Is cardiovascular disease the leading cause of mortality for patients with diabetes?

There is a great risk for various cancers in people with diabetes such as pancreatic cancer and others related to insulin resistance that are part of the diabetes syndrome. Yet in terms of causes of death cardiovascular disease is number one. The other causes are not that far behind and rising due to coexistence of obesity and the ageing population.

What should be the biggest priority in these patients: controlling blood sugars or reducing weight?

Reducing weight is a major advantage. The two classes of drugs that show cardiovascular advantage also cause weight reduction—that is another beneficial effect of these drugs. Whereas the older ones such as sulfonylurea and insulin made people put on weight.

Are there any guidelines available to aid healthcare physicians in making the right clinical choices?

The American Diabetes Association and the European Association for the Study of Diabetes regularly publish a joint position statement that updates the use of glucose-lowering therapies. They are fairly laissez faire and recommend metformin as first-line treatment and then any second-line treatment after that. It is a bit more up-to-date than NICE at present.

What happens when first-line treatments don’t work?

If the patient has cardiovascular disease, it should now be taken on board which new agents have evidence of positive cardiovascular disease outcomes. If the patient has no cardiovascular disease then we have choice of all potential drugs including thiazolidinediones and DPP-4 inhibitors. Insulin generally remains a treatment of last resort.

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Alison Bloomer

Conflict of interest: none declared.

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References

1. Low Wang C, Hess C, Goldfine A. Clinical update: cardiovascular disease in diabetes mellitus. J Am Coll Cardiol. 2016; 60: e44–e164
2. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and Cardiovascular Disease. A Statement for Healthcare Professionals From the American Heart Association. Circulation 1999; 100: 1134–46
3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–28
4. Neal B, Perkovic V, Mahaffey K, et al for the CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377: 644–57
5. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375(4): 311–22
6. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375: 1834–44
7. The Look AHEAD Research Group. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes. N Engl J Med 2013; 369: 145–54